Neuromuscular Junctional Disorders - medIND

Special Article

Neuromuscular Junctional Disorders A.S. Girija and V.V. Ashraf Department of Neurology, Malabar Institute of Medical Sciences, Calicut, Kerala, India

ABSRACT Neuromuscular junctional disorders (NMJ) in children are distinct entity . They may be acquired or hereditary. They pose problem in diagnosis because of the higher occurrence of sero negative Myasthenia Gravis (MG )cases in children. The identity of MusK antibody positivity in a good percentage of sero negative cases further adds to problems in diagnosis. The Congenital Myasthenic Syndrome (CMS) which are rare disorders of hereditary neuromuscular transmission (NMT) has to be differentiated because immunotherapy has no benefit in this group. Molecular genetic studies of these diseases helps to identify specific type of CMS which is important as other drugs like Fluoxetine, Quinidine are found to be effective in some.In infancy , all can manifest as floppy infant syndrome .The important key to diagnosis is by detailed electrophysiological studies including repetitive nerve stimulation at slow and high rates and its response to anticholinesterases and estimation of Acetyl choline receptor antibodies. Other causes of neuromuscular transmission defects viz. snake venom poisoning and that due to drugs are discussed. [Indian J Pediatr 2008; 75 (7) : 699-702] E-mail: [email protected] Key words : Myasthenia gravis; Myasthenic syndrome

Neuromuscular junction (NMJ) disorders result from destruction, malfunction or absence of one or more key proteins involved in neuromuscular transmission (NMT). The most common pathology is antibody mediated damage or down regulation of ion channels or receptors, resulting in myasthenia gravis (MG). A second important group of disorders are the Congenital Myasthenic Syndromes CMS caused by mutations in genes which encode NMJ proteins.1 Fig 1 shows the normal NMJ. The acetyl choline receptor (AChR) and the various proteins at NMJ are depicted in Fig. 2. About 25% of patients with MG present in childhood and adolescence.2 Indian study of 77 children with MG has revealed an equal sex ratio.3 MG is caused by serum antibodies(produced mainly by B cells) binding to the nicotine AChR on the post synaptic surface of the NMJ leading to its loss. T-cells as well as thymus have role in pathogenesis. The different antibodies which occur in MG AChR antibodies occur in 80 to 90% cases with MG. In children, it is less, coming to 50% only. The other antibodies which are detected in MG include anti MuSK (Muscle specific Kinase) antibodies (Anti IgG). This has

Correspondence and Reprint requests : Dr. A.S. Girija ‘Marathakam’, 5/2980 D, Thirithiyad, Puthiyara PO, Calicut, Kerala-673004. Phone : 0495-2722494 [Received January 5, 2006; Accepted April 10, 2008]

Indian Journal of Pediatrics, Volume 75—July, 2008

Fig. 1. Normal neuromuscular junction

been found in 40% of patients with generalized MG who are seronegative. (for ACh R antibodies). A third type of antibodies detected in MG is the antibodies to striated muscle.4 In fact, acquired MG is classified based on antibodies. (Table 1) CLINICAL FEATURES The common features of NMJ disorders are 1) Fatigability, generalized muscle weakness worsened by exertion.2) 699

A.S. Girija and V.V. Ashraf twang and slurred speech. Infection can precipitate symptoms. Acute respiratory failure can be a presentation.

Fig. 2. Synaptic and post synaptic molecules at NMJ (AChE – Acetyl cholinesterase, AChR- Acetyl choline receptor) TABLE 1. Classification of NMJ Disorders Acquired NMJ disorders Myasthenia gravis Seropositive Anti AChR Positive Anti MuSK Positive Drug induced (pencillamine) MG with Thymoma Neonatal MG Sero Negative AChR Negative Snake venom Botulinum Toxin

Congenital and familial Congenital Myasthenic Syndrome Pre synaptic CMS with episodic apnea Paucity of synaptic vescicles simulating Lambert Eaton Synaptic AChE deficiency Post synaptic Kinetic abnormalities with normal, reduced or increased AChR MuSK, Rapsyn, Agarin, Plectin mutations

Anti Musk Antibody Positive MG : Many of the patients with anti MuSK antibodies have prominent oculobulbar symptoms with nasal speech and facial weakness (100%). Isolated weakness of extensors of the neck and respiratory muscles without extra ocular palsy can occur. Pure ophthalmoplegia is almost unknown. So also is the association of thymoma. They have more severe disease with frequent respiratory paralysis and are less likely to improve after thymectomy. Limb involvement is less. Facial atrophy, and tongue fasciculations has been observed. The response to anticholinesterases is not satisfactory.5 Hence, neostigmine test can be equivocal or negative. Sensitivity of repetitive nerve stimulation test (RNS) is less in these cases. Neonatal myasthenia gravis (NMG). Placental transfer of maternal anti AChR antibodies to the fetus can cause transient neonatal MG in about 10% of newborns of myasthenic mothers. Two clinical forms of NMG have been described: typical (71%) and atypical (29%). Clinical features of the atypical form include the presence of arthrogryposis multiplex congenita (AMC) in the fetus or newborn .The severity of AMC in the infant is variable and does not co-relate with either the severity of maternal MG during pregnancy, or to parity. At birth or shortly afterwards, babies present with hypotonia, respiratory distress, and feeding difficulties which usually resolve in 4 to 6 weeks. 6 A high fetal/adult AChR Ab ratio is correlated with the occurrence of NMG in the first child. CLINICAL TESTS FOR ASSESSMENT

Ophthalmoplegia 3) Fluctuations and diurnal variations. Delayed milestones can occur in CMS. The muscle weakness is predominantly for proximal limb muscles, which manifests as difficulty in walking, climbing, running, getting up from squatting position. Ophthamoplegia starts as bilateral ptosis, squint and double vision. Ptosis may be unilateral. Bulbar muscle weakness manifests with difficulty in swallowing, nasal

Fatigability is demonstrated by asking the patient to sustain upgaze for a minimum of 60 seconds which worsens ptosis. Placing ice over lids improves ptosis. Variability of the findings is an important feature of myasthenia. Degree of ptosis and squint varies from time to time. Bulbar fatigue is demonstrated by supporting of

TABLE 2. Differentiating features of Myasthenia gravis and Congenital Myasthenic syndrome Distinctive Features Familial occurrence Pattern of inheritance Consanguinity Age of onset

Spontaneous remission Association of other autoimmune diseases Characteristic facial appearance apart from ptosis Response to immuno modulatory treatment

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Myasthenia Gravis Extremely rare (2-5%)

Unknown below 2 years, except transient neonatal myasthenia gravis Can occur Favours diagnosis Nil Positive

Congenital Myasthenic Syndrome Common Mostly Autosomal recessive Favours diagnosis Neonatal period to adulthood

Does not occur Not seen Elongated face, prognathism, high arched palate Nil


Neuromuscular Junctional Disorders the jaw on repeated chewing, and slurring of speech on continued counting. Limb fatigability is assessed by the duration for which arms can be kept outstretched, and the number of times the patient can getup from squatting position. Predominant proximal muscle weakness is noticed in myasthenia. Reflexes are preserved. Atrophy of muscles is extremely rare. After demonstration of fatigability, it is important to do the prostigmine test. As edrophonium hydrochloride is not available in India, injection of prostigmine S/C or I/M at a dose of 0.04mg/ Kg is given to note the recovery of the fatigued muscle. Usually, recovery of the ptosis or slurring of speech is looked into. I/V Atropine must be given prior to prostigmine to counteract the cholinergic adverse effects like abdominal colic. A positive response occurs in 20 to 30 minutes and the response is unequivocal. There is a low but definite risk of bradycardia and hypotension associated with the test. Hence, it should be done with facilities for resuscitation. False positive result can occur in Amyotrophic lateral sclerosis , progressive external ophthalmoplegia, poliomyelitis, peripheral neuropathy, brainstem lesions and oculomotor denervation. False negativity may occur in long standing external ophthalmoplegia due to MG.7 The different and salient clinical features which help to distinguish Myasthenia and CMS are listed in table II. Special investigations and therapeutic trial of steroid may be required at times to differentiate the two. The author’s

article8 is a report of 19 cases (largest study of CMS from India),7 sporadic and 12 being familial diagnosed at 1.5 to 26 years. All had ophthalmoplegia. Three had prognathism. Second degree consanguinity was observed in 4 sporadic and 4 familial cases. Anti cholinergics was found to be effective in all. The differentiating features of various CMS are listed in Table 3. NON ELECTROPHYSIOLOGICAL INVESTIGATIONS It is essential to send serum for AChR antibodies, antiMuSK antibodies in all NMJ disorders. Special tests like thyroid function tests, ANA, RA factor have to be done when associated collagen vascular disease is suspected. An X-ray chest lateral or CT thorax to pick thymoma is done in MG. Thymoma is rare in children. ELECTROPHYSIOLOGICAL TESTS Repetitive nerve stimulation (RNS) at slow rates(3HZ) in the clinically weak muscles, (deltoid or trapezius ) is done. In pure ocular and bulbar affection, levator palpebrae superioris, nasalis and or facial muscle is tested. A decrement response is diagnostic of NMJ disorder.A decrement at low rates of stimulation and increment at high rate(>200%) is diagnostic of LEMS.9 Single fibre EMG is more sensitive than RNS.

TABLE 3. Congenital Myasthenic Syndrome-Other Features Presynaptic

Synaptic

Postsynaptic

Disorders

CMS with episodic apnea One with reduced quantal release

End plate ACh deficiency

Frequency Defect

8% In1 defect in ACh synthesis and packaging In2 defect in quantal release Positive

26% ACh accumulates leading to receptor damage

Kinetic defects ACh R deficiency MuSK, Plectin, Agarin mutations 76%

+ In1 it will be positive only during exacerbations _

+

I/V Prostigmine test RNS at 2HZ Repetitive CMAP to single stimulus

May worsen

No effect in slow channel syndromes. In others, positive +

Present

Present in slow channel syndrome

Small endplate region. Absent AchE staining. Number of AChR reduced Same

Small endplate region in slow channel syndrome. Destruction of junctional folds Tubular aggragates in some Slow channel cases Qunine and Fluexetine in slow channel syndrome 3,4 DAP in fast channel syndrome α,β,δ,εsub unit mutations in slow channel syndrome. 2p and q, 17pand q in slow channel 9q31 in MusK

Morphology, NMJ IgG/ complement absent in CMS

Small synaptic vescicles. Normal post synaptic folds and receptors

Muscle Biopsy

Type I fibre predominance and TypeII atrophy

Treatment Anti ChE

Effective

Anti ChE not useful Ephedrine 50mg tds effective

Molecular genetics

ChAT protein, 10q11.2 in1

ColQ 3p25

CMAP – Compound muscle action potential; DAP – Diamino pyridine


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A.S. Girija and V.V. Ashraf OTHER TESTS Electron microscopic study of anconeus or inter costal muscles are done in specialised laboratories for histochemical, cytochemical and immunocytochemical localization of AChE, AChR, and for identification of endplate-Specific, 125-1a BGT-binding sites, electrophysiological studies for measurement of Miniature endplate potential, Miniature endplate current etc. Molecular genetical studies can diagnose most of CMS.10 Drug induced myasthenia Drugs can precipitate 1) acute myasthenic symptoms with preexisting NMT problems The anti AChR is negative in such cases. 2) Drugs are known to worsen cases of MG. e.g., Antibiotics: Neomycin; Streptomycin; Gentamicin; Colisitins; ? Kanamycin Anti-rheumatic: Prednisone; Chloroquine NMJ blockers: Curare; Nondepolarizing -Vecuronium; botulinum toxin. Others: Quinidine; Procainamide; Procaine, beta blockers 3) Slow onset with drugs which is immune mediated. This occurs following Pencillamine therapy. Anti AChR antibody may be positive. This often reverts on stopping the drug.11 Neuromuscular paralysis in snake venom poisoning Alpha bungarotoxin of krait and alpha cobra toxin binds to AChR. Ophthalmoplegia, neck muscle weakness, limb weakness and respiratory failure can occur within 6 hours of bite. Evidence of presynaptic blockade has been demonstrated in some cases and in others post synaptic defect with response to anticholinesterases. The definitive therapy is antitoxin.12 Rare NMJ disorders and their differentiation Lambert Eaton Myasthenic syndrome(LEMS), a presynaptic disorder of NMT occurs usually secondary to oatcell carcinoma and hence is rarely seen in children. An idiopathic and CMS simulating LEMS has also been reported. The symptoms are fatigue which paradoxically improves with exercise. Ocular muscles are affected only rarely, unlike MG and reflexes are absent. Autonomic manifestations like dryness of mouth, pupillary abnormalities coexist. Antibodies to Voltage Gated Calcium channel can be detected in the paraneoplastic subtype.13 Botulinum toxin affects presynaptic NMT. The complaints are of acute onset of dry mouth and blurred vision progressing to diplopia, dysphagia and weakness of limbs.Pupillary dilatation, ophthalmoplegia, bulbar and respiratory weakness with preserved reflexes and normal sensations is noted. Symptoms are precipitated by taking canned food and manifest in 12 to 36 hours. There is no decrement at low rates of stimulation but increment of CMAP occurs at 20-50Hz. Tensilon test is negative.14 Botulism poisoning is rarely reported in India. 702

The non NMJ disorders which simulate myasthenia As neonatal myasthenia gravis and the different CMS and MG present in infancy or childhood, they may superficially resemble a variety of diseases. The congenital myopathies which mimics NMJ disorders, because of the facial and jaw muscle involvement producing elongated face and prognathism along with ophthalmoplegia are nemaline myopathy and myotubular myopathy. Refexes are reduced or absent in the myopathies. Spinal muscular atrophy type 1 and 2 have marked muscle wasting and areflexia and bulbar involvement but ophthalmoplegia is not seen. Mitochondrial cytopathy produces muscle fatigability and ophthalmoplegia. Polymyositis is associated with subacute onset of generalized muscle weakness with preserved reflexes but ophthalmoplegia is uncommon.15 REFERENCES 1. Engel AG. Congenital myasthenic syndromes. Neurological Clinics of North America 1994; 12 : 401-436. 2. Batocchi AP, Evote A, Palmisani MT, Lommato M, Bartoccioni M, Tonali P. Early onset myasthenia gravis: clinical characters and response to therapy. Europ Jl of Paed 1990; 150 : 66-68. 3. Ashraf VV, Taly AB, Veerendrakumar M,Rao S Myasthenia gravis in children: a longitudinal study. Acta Neurol Scand 2006; 114 : 119-123. 4. Lindstrom JM. Acetylcholine receptors andmyasthenia. Muscle and Nerve 2000; 23 : 453-477. 5. Hoch W, McConville J, Helms S et al. Auto-antibodies to the receptor tyrosine kinase MuSK, in patients with myasthenia gravis without acetylcholine receptor antibodies. Nature Med 2001; 7: 365-368. 6. Papazian O. Transient neonatal myasthenia gravis. J Child Neurology 1992; 7 : 135-141. 7. Thanvi BR, Lo TCN. Update on myasthenia gravis. PGMJ 2004; 80 : 690-700. 8. Girija AS, Somanath V, John JK, Jose J. Congenital myasthenic syndrome – A report of nineteen cases. Annals of Indian Academy of Neurol 2001; 4 : 71-75. 9. Somnier FE, Trojaborg. Neurophysiological evaluation in myasthenia gravis. A comprehensive study of a complete patient population. Electroencephalogr Clin Neurophysiol 1993; 89 : 73-87. 10. Engel AG, Lambert LH, Gomez MR. A new myasthenic syndrome with endplate acetyl cholinesterase deficiency small nerve terminal and reduced acetylcholine release. Ann Neurol 1997; 1 : 315-330. 11. Barrons RW. Drug induced neuromuscular blockade and myasthenia gravis. Pharmacotherapy 1997; 17 : 1220-1232. 12. Sanmuganathan PS, Senanayaka N. Myasthenic syndrome of Snake envenoming : a clinical and neurophysiological study. Neurology 1991; 41 : 42 13. Middlison P, Davis Mills KR. Distribution of electrophysiological abnormality in Lambert Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 1998; 65: 213-217. 14. Schreiner MS, Field E, Ruddy R. Infant botulism. A review of 12 years experience at the children’s hospital of Philadelphia Paediatrics 1991; 87 : 159-165. 15. Khwaja GA, Chowdhary D, Gupta M. Congenital myasthenic syndrome : report of 4 cases and brief review of literature. Neurol India 2000; 48 : 266-271
